High activities of BACE1 in brains with mild cognitive impairment.

We recently discovered elevated β-secretase 1 (BACE1) activity in brains with sporadic Alzheimer disease (AD). Moreover, we also found high levels of BACE1 enzymatic activity in the cerebrospinal fluid from patients with both mild cognitive impairment (MCI) and AD. These results suggest that elevation of BACE1 enzymatic activity may occur early or may contribute to AD. We therefore examined whether BACE1 enzymatic activity was changed in MCI brains. BACE1 activity and tumor necrosis factor (TNF)-α levels were measured by enzymatic assay and ELISA in the temporal cortex from 18 patients with clinically well-characterized AD, 18 patients with MCI, and 18 healthy controls. We found a significant increase in BACE1 activity and protein level in brains of MCI and AD patients. Moreover, increased BACE1 activity correlated with plaque numbers and cognition status. We also found an increase in TNF-α in MCI brains. In vitro study revealed that TNF-α rather than other cytokines can up-regulate BACE1 protein expression. These findings suggest that BACE1 increase occurs early in MCI and is possibly induced by TNF-α and that BACE1 enzymatic activity may be important for conversion of MCI to AD.